FI64585C - FOERFARANDE FOER FRAMSTAELLNING AV ETT TERAPEUTISKT AKTIVT ARYLPYRIDAZINYLHYDRAZINSALT - Google Patents

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National Board of Patents and Registration (44) Date of registration and registration

Patent and registration authorities Antökm utiagd och uti.skriften pubiicend. uo. 0 j (32) (33) (31) Requested front - Begird pr lorit et 0U. 08.78

England-England (GB) 32312 (71) Smith Kline & French Laboratories Limited, Mundells, Welwyn Garden City, 1 le rt fo rd s hi re, England -England and (GB) (72) Brimi Eric Burpitt, Stevenage, Hertfordshire, Michael James Graham,

Welwyn Garden City, Hertfordshire, Anthony Maitland Roe, Hatfield, Hertfordshire, English-Fhgland (GB) (7¾) Berggren Oy Ab (5U) relates to a process for the preparation of a new arylpyridazinylhydrazine salt.

Belgian Patent 830,158 describes a group of arylpyridazinylhydrazine compounds having the basic structure of formula I:

aOCH2CHOHCH2NHR

NHNH 2 in which the rings may have a variety of named substituents, R is isopropyl, tertiary butyl or phenylethyl; the compounds have been found to both act as adrenergic β2 inhibitors and to dilate blood vessels. In these compounds, the carbon atom to which the hydroxyl group is attached is asymmetric, so that normal synthesis methods give a racemate containing equal amounts of each of the 2,64585 optical isomers. Separately there are e.g. said compound of structure I wherein R is tertiary butyl is called 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hyurazinepyridazine (II) and a process for its preparation is disclosed in Belgian Patent 830,158 in Example 2. The present invention relates to a specific form of this compound. According to Belgian Patent 830,158, these compounds may be present in pharmaceutical compositions for therapeutic use either in their basic form or as salts of pharmaceutically acceptable acids, such as salts of hydrochloric, bromine, iodine, sulfuric, acetic, citric or maleic acid. The only form in which compound II is administered is the hemisulphate hemihydrate of Example 2 of Belgian Patent 830,158, the other specific compounds being prepared as amorphous citrate, sulphate or free base.

The structure of Compound II, as well as that of the compounds mentioned in Belgian Patent 830,158, has three basic features: a hyarazine group, a heterocyclic ring in which two nitrogen towers are bonded to each other as adjacent ring atoms, and a secondary amino group, and the compounds can form mono-, mono-, mono- or tris - salts and salts with dibasic acids, including hemisulphate. The compounds have also been found to readily form salts which, as solid crystals, may contain a crystallization solvent such as the hemisulphate hemihydrate of Compound II.

It has now been found that the specific form of the racemate of Compound II has a valuable pharmaceutical and medical use that has not been shown to exist in many of the other compounds studied.

It has been found that the racemate of compound II forms a crystalline dihydrochloride monohydrate, which is a particularly stable, non-hygroscopic solid which can be well tableted and which can be uniformly recrystallized in good volume efficiency from a suitable solvent: such a crystalline solid contains about 1.1 moles (4.5% by weight) of water of crystallization, this amount of water has been obtained by analysis by both the Karl Fischer method and the thermogravimetric method (Perkin-Elmer TGS / 1 hot scale). In contrast, the racenic hemisulphate hemihydrate of Compound II has been found to deteriorate 3,645,85 if it has to stand, either due to hygroscopicity or for some other reason; further after crystallization under standard conditions, the water content of the amount of solvent contained in the crystals of this hemisulphate varies unpredictably. Therefore, the hemisulphate salt cannot be sold in solid, oral doses, such as tablets or capsules filled with powder. Furthermore, aqueous dihydrochloride solutions are more stable than aqueous hemisulphate solutions. It has also been found that high doses of dihydrochloride monohydrate administered orally to mammals cause diarrhea to a lesser extent than when equivalent amounts of hemisulphate hemihydrate are administered.

Other salts of the racemate of compound II were also studied: monohydrochloride was a non-crystallising oil, trihydrochloride was obtained as a crystalline but recrystallization was difficult and its aqueous solutions are not very suitable for intravenous administration because they are very acidic :, dihydrobromide was an oil which crystallized and the analytical data obtained therefrom were poor, no di-hydroiodide could be recrystallized, and no sample was obtained from which satisfactory analytical data were obtained. Salts of the racemate of Compound II prepared using molar equivalent amounts of citric, maleic or acetic acid and a salt prepared using twice the molar amount of acetic acid were not allowed to crystallize. Salts prepared from many other pharmaceutically acceptable acids, for example, orthophosphoric, palmitic, stearic, benzoic, amber, fumaric, malonic, glutaric, itaconic, glycol, D, L-paint, The diprotonated salts of L (-) - tartaric, aspartic and pamoic acid were all oils that could not be crystallized.

The dihydrochloride monohydrate forms colorless needles whose melting point cannot be considered as a reliable physical value characterizing the compound because the compound decomposes giving up water and the transition from the solid phase to the liquid phase cannot be clearly determined. By determining the melting point in an open capillary tube so that the initial temperature was 130 ° C and the temperature was allowed to rise in 3 ° per minute, the compound melted so that melting occurred over several degrees, at any temperature between 154-168 ° C. When the compound was subjected to DSC-TG (differential scanning calorimetric thermogravimetric analysis) in an open vessel with a temperature rise of 10 ° per minute, two transition temperature ranges were observed: in the temperature range 110-145 ° C, 4.2-4.3 weight loss and 0.2% weight loss in the 150-180 ° C range; melting occurred during this second weight loss normally in the range of 154-159 ° C. The weight loss per mole of water would be 4.27% and the total weight loss was consistently greater than this value, about 4.5%.

When the dihydrochloride monohydrate was subjected to DSC-TG analysis in a sealed vessel, it was found to melt at 143 ° C.

When a 5 mg sample of dihydrochloride monohydrate was heated at 100 ° C for 1.5 hours in a DSC-TGA apparatus, a weight loss of 4.31% was observed. The sample was allowed to cool to room temperature and brought to normal pressure for 15 minutes and re-analyzed. When the device was programmed to rise from 40 ° to 180 ° in 10 minutes, a weight loss of 3.89% occurred in the temperature range of 110-145 ° C. This indicates that water is released from the monohydrate when heated, and upon cooling, the anhydrous dihydrochloride absorbs water from the moisture in the air and is converted back to the monohydrate.

When 15 g of the dihydrochloride monohydrate sample was stored (a) for 16 hours at 40 ° C, (b) at room temperature above phosphorus pentoxide for 16 hours, (c) at room temperature and 0.5 mm Hg above phosphorus pentoxide for 16 hours, a negligible (less than 0.3%) ) weight loss. When 0.6 g of the dihydrochloride monohydrate sample was stored at 22 ° C and 90% humidity for 3 weeks, the weight of the sample increased by 0.7%. Thus, it was found that the dihydrochloride monohydrate is a stable form under normal temperature and humidity conditions and is suitable for solid pharmaceutical compositions.

Belgian patent 830 158 discloses the preparation of the free base of compound II and its acid addition salts.

In the process of this invention, racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinepyridazine dihydrochloride monohydrate is prepared by administering racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) reacting phenylf7-6-hydrazinipyridazine or another acid addition salt of this compound with the amount of hydrochloric acid and water required to form the dihydrochloride monohydrate, and the dihydrochloride monohydrate is isolated as a solid separate salt. Two equivalents of hydrochloric acid are required for each equivalent of pyridazine base, although less or more hydrochloric acid may be used, for example as little as 1.8 or as much as 2.2 molar equivalents if monohydrochloride or trihydrochloride and less dihydrochloride monohydrate are formed. If an aqueous solution of dihydrochloride is prepared in the initial powder, the amount of hydrochloric acid required depends on the concentration and is such that it causes a change in pH from 3 to 4. Excess water can be used to form the monohydrate and the excess can be removed when isolating the product.

Preferably, the hydrazine pyridazine solution is placed in a liquid medium with the required amount of hydrochloric acid and water to give a precipitate of solid dihydrochloride monohydrate particles which can be isolated. The liquid medium may be water or an organic solvent, for example dichloromethane, ethanol, n-propanol, isopropanol or t-butanol. The precipitation of solid particles directly from the medium can be enhanced, the precipitation can be effected by the addition of hydrochloric acid or water, as is the case if hydrochloric acid is added to a dichloromethane solution of pyridazine base or water is added to an n-propanol solution of anhydrous dihydrochloride. Precipitation can also be effected by cooling the dihydrochloride monohydrate solution, for example if the solvent is n-propanol or t-butanol containing a small excess of water, for example n-propanol containing 7-9% by weight of water. Precipitation can be effected by removing the solvent into the gas phase, for example by evaporation under reduced pressure or by adding a diluent which reduces the solubility of the dihydrochloride monohydrate in the solvent medium; the diluent may be, for example, tetrahydrofuran, ether or toluene.

Solvent residues (including excess water) are preferably removed from the isolated particles produced by heating, for example with flowing gas at 50-60 ° C, or by heating under reduced pressure, for example 0.5 mm Hg, at 90 ° C. Such treatments may cause loss of hydration water, or a portion thereof; if the water of hydration of the product is lost, the product is allowed to hydrate again on cooling, this can be achieved simply by means of moist air.

6 64585

Hydrochloric acid can be obtained by adding aqueous hydrochloric acid or anhydrous hydrochloric acid and exchanging the anions of the various salts of Compound II. Anion exchange can be accomplished by contacting a solution of a salt of Compound II with an anionic resin or by adding a soluble chloride of a metal that initially forms an insoluble salt with the anion associated with Compound II, e.g., the hemisulphate of Compound II can be converted to the dihydrochloride. adding a concentrated calcium chloride solution to the hemisulphate solution of Compound II; calcium chloride is added in 1 molar equivalent per two molar equivalents of hemisulphate, insoluble calcium sulphate is filtered to give a monohydrochloride solution of compound II to which a molar equivalent of hydrochloric acid is added to give the dihydrochloride.

This invention also relates to pharmaceutical compositions comprising the dihydrochloride monohydrate and a pharmaceutically acceptable diluent or carrier, and to a process for making such pharmaceutical compositions: the dihydrochloride monohydrate is contacted with a diluent or carrier. Such compositions may be in solid or liquid form for oral administration or may be in the form of intravenous solutions. These pharmaceutical compositions are prepared in a conventional unit dosage form by administering to a pharmaceutically acceptable diluent or carrier such a non-toxic amount of racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinepyridazine dihydrochloride monohydrate monohydrate monohydrate monohydrate monohydrate monohydrate monohydrate monohydrate monohydrate monohydrate monohydrate monohydrate monohydrate blood pressure. Preferably, the composition contains from 50 mg to 300 mg of active ingredient per dosage unit. The solid dihydrochloride monohydrate can be formulated by either (a) forming a capsule or (b) mixing it with a solid diluent or carrier and formulating the mixture into a dosage unit form, or (c) dispersing the dihydrochloride monohydrate in a liquid diluent or carrier. The pharmaceutical compositions may be made either by mixing, granulating and compressing the solids into tablets which may be coated by spraying, or the compositions may be made by mixing and dissociating the ingredients into a liquid preparation. Preferably, the mixtures are made by a process in which the wet ingredients do not come into contact with salts of transition or heavy metals, especially iron salts. with.

7 64585

The pharmaceutical carrier may be a solid or a liquid. For example, the solid carrier may be lactose, corn starch, potato starch or modified starch, dicalcium phosphate, Terra Alba, sucrose, celluloses, talc, gelatin, agar agar, pectin, acacia, magnesium stearate and stearic acid. The liquid carrier may be, for example, syrup, peanut oil, olive oil, alcohol, propylene glycol, polyethylene glycols and water.

If a solid carrier is used, the composition may be formulated as either a tablet or a capsule containing a powder or granules, a medicated bead or a lozenge. The amount of solid carrier per dosage unit is generally from about 25 mg to 300 mg. If a liquid carrier is used, the mixture may be in the form of a syrup, emulsion, multiple emulsion, sterile injectable solution or aqueous or non-aqueous solution, or liquid suspension. Other additives such as preservatives, antioxidants or antibacterial agents and / or flavoring, or coloring agents may also be included. Sterile solutions can be prepared as either ampoules, multidose vials, or unit dose systems.

The following examples illustrate the invention. In the examples, temperatures are given in degrees Celsius (° C).

Example 1

Racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-chloropyridazine hydrochloride (10 g) was added with stirring to hydrazine hydrate (40 ml, 100%) and the mixture was heated under reflux for 2 hours. Upon cooling to 30 °, 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinepyridazine base separated as an oil and the mixture was extracted with dichloromethane (3 x 10 ml) and the extract was washed several times with a small amount of water until no more hydrazine was removed. had been shown by thin layer chromatography, silica gel was used as adsorbent, the plates were developed with chloroform / methanol solution (4: 1) and sprayed with potassium iodiplatin reagent; if there is even a little hydrazine left, a light circle appears around the blue dot obtained from hydrazine pyridine.

There was thus obtained a solution of racemic hydrazine pyridazine base (8.93 g, 0.027 mol) in dichloromethane (30 ml). To this solution were added n-propanol (40 ml) and concentrated hydrochloric acid (4.45 ml, 0.054 mol) and the solution was distilled until the steam temperature was 85 ° 8 64585 (to remove dichloromethane), water (2 ml) was added and the solution was allowed to cool to room temperature. . The dihydrochloride monohydrate crystals formed during cooling were filtered off and heated in an oven under reduced pressure (0.5 mm Hg) at 90 ° for 6 hours to remove the solvent, after which the crystals were allowed to stand for four hours in dry air, during which time the crystals bound sufficiently water and monohydrate. 0 g) complete formation was confirmed.

Example 2

By the method of Example 1, crystals of dihydrochloride monohydrate were prepared from 200 g of racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-chloropyridazine hydrochloride, which was dried under a gas stream at 60 ° for 1.5 hours. and dihydrochloride monohydrate (190 g) was obtained.

Example 3

To a dichloromethane solution (3.0 L of dichloromethane) of racemic hydrazine-pyridazlin base (789 g, 2.35 mol) obtained by the method of Example 1 was stirred concentrated hydrochloric acid (SG 1.18, 392 mL, 4.7 mol) over 10 minutes with vigorous stirring and the vessel was stirred. while cooling from the outside. The mixture was stirred in an ice-water bath for 1 hour, and then the precipitated solid dihydrochloride monohydrate was separated. The collected undried solid was washed with dichloromethane and recrystallized from n-propanol (3.2 liters), the recrystallized monohydrate was heated under reduced pressure at 90 ° for 6 hours to remove the solvent, then allowed to stand on dry medium for 16 hours to ensure complete conversion to the monohydrate (800 g), m.p. 157-160 °.

Example 4

To a solution of racemic hydrazine pyridazine base in dichloromethane (7.5 liters) obtained from racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-chloropyridazine hydrochloride (1.98 kg) by the method of Example 1 was added concentrated salt (conc. SG 1.18, 0.912 liters), the vessel was simultaneously cooled from the outside. The solid formed on cooling was filtered and air dried at room temperature overnight. The partially dried material (2.7 kg) was suspended in n-propanol (16 liters) and the mixture was distilled until the temperature reached 93 °. There was thus obtained a solution of 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinepyridazine dihydrochloride (1.95 kg) (10 liters) in 64585; to this solution was added water (0.5 liters) and the mixture was allowed to cool to room temperature, the solid crystallized material was collected, washed well with n-propanol and dried at 90 ° C under 0.5 mm Hg and allowed to stand on dry medium at room temperature. at 16 hours, which ensured complete conversion of the product to the dihydrochloride monohydrate (1.94 kg), m.p. 163-166 ° C.

Example 5

A mixture of hydrazine hydrate (64% hydrazine, 131 kg) and racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-chloropyridazine hydrochloride (30 kg) was heated under reflux for 2.5 hours and allowed to cool. 20 ° C. Dichloromethane (74 liters) was added to the mixture, the mixture was stirred and the dichloromethane layer was separated. The hydrazine phase was extracted twice with dichloromethane (20 and 16 liters), the combined dichloromethane extracts were washed five times with water. Aqueous hydrochloric acid (SG 1.18, 15.7 kg) and n-propanol (120 liters) were added to the dichloromethane solution, and the mixture was distilled until the temperature in the vessel was 93 °. The mixture was allowed to cool to 15-20 °, stirred for 30 minutes and the solid crystals were centrifuged off and washed with n-propanol. The solvent was removed by placing the solid in a compressed air oven for 36 hours. The solid was passed through a filter (No. 6 mesh) and dried with a gas stream at 55 ° for 3 hours to give the product racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6- hydrazine pyridazine dihydrochloride monohydrate (27.2 kg).

The water content of the mixture is checked by the Karl Fischer method, preferably before the n-propanol solution is allowed to cool, and if the water content is not 7-9% by weight, it must be arranged in this range either by adding water or by adding n-propanol and further distilling the mixture.

Example 6

Racemic 6- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -3- (2h) -pyridazinethione (1 g) was added with stirring to hydrazine hydrate (4 ml) and heated under reflux for 1.5 hours. The solution was cooled to 25-30 °, whereupon 3- [2- (3-t-butylamino-2-hydroxy-10,64585 propoxy) phenyl] -6-hydrazinepyridazine base separated as an oil.

To dissociate the base and organic layer, dichloromethane (10 mL) was added, shaken, separated and washed with water (3 x 1 mL). The organic phase was dried over magnesium sulphate and the solvent removed by evaporation to leave a base as a brown oil (0.98 g, 2.9 mmol). This oil was dissolved in ethanol (3 mL) and concentrated hydrochloric acid (SG 1.18, 0.48 mL, 5.8 mmol) and ether (3 mL) were added. The crystals were filtered off and dried in a vacuum oven at 90 ° and 0.5 mm Hg for 16 hours, then allowed to extract sufficient moisture from the air to give the dihydrochloride monohydrate, m.p. 156-164 °.

Example 7

The oily racemic free 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazine-pyridazine base (4.8 g, 0.014 mol) obtained by the method of Example 6 was dissolved in t-butanol (10 ml). ° and concentrated hydrochloric acid (SG 1.18, 2.4 ml, 0.024 mol) was added, the mixture was heated to boiling and water was added dropwise until complete dissolution. The solution was allowed to cool to 0 ° overnight, whereupon the dihydrochloride monohydrate crystals precipitated, then filtered and dried at 90 ° and 0.5 mm Hg for 6 hours and allowed to dry in air at room temperature to give the dihydrochloride. monohydrate, (4.0 g), m.p. 167-170 °.

Example 8

The oily racemic free 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinopyridazine base obtained by the method of Example 6 was dissolved with heating in n-β-opanol (25 ml) and concentrated hydrochloric acid (SG 1.18 , 2.52 mL, 0.025 mol); the resulting solution was cooled to 20 ° and the precipitated crystals were filtered to give the product dihydrochloride monohydrate, (3.5 g), m.p. 154-160 °.

Example 0

Racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -7-6-hydrazinepyridazine homosulfate hemihydrate (100 mg) was dissolved in 0.1 N hydrochloric acid (1.27 mL) and added to the solution at room temperature to a minimum. calcium chloride hexahydrate (30 mg) dissolved in water. The calcium sulfate was removed by filtration, and the solution was evaporated under reduced pressure to give a solid residue (101 mg), which was recrystallized from n-propanol and allowed to stand in dry air to give the dihydrochloride monohydrate (66 mg).

Example 10

Racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinepyridazine hemisulphate hemihydrate (48.6 mg, 0.123 mmol) was dissolved in distilled water (10 mL) and the solution was passed through an Amberlite IRA-400 column ( 10 ml, in chloride form), distilled water (30 ml) was used as the elution solution. Amberlite IRA-400 is a quaternary ammonium ion exchange resin with 8% polystyrene-divinylbenzene adhered to the matrix by crosslinking. Hydrochloric acid (1.0 N, 0.124 mL) was added to the eluate, the mixture was lyophilized and the dried powder was further dried at 80 ° and 1 mm Hg for 20 hours. This solid was recrystallized from n-propanol with 8% by weight water; the product was dried at 80 ° and 1 mm hg for 8 hours and allowed to stand in undried air to give the dihydrochloride monohydrate, which suffered a weight loss of 4.94% on a DSC-TG analyzer.

Example 11

For oral administration, a pharmaceutical composition in tablet form was prepared by the following method. Racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinepyridazine dihydrochloride monohydrate (106 parts) was added to a mixture of microcrystalline cellulose (83 parts) and microfine quartz (1 part), and the mixture was stirred. . Magnesium stearate (2 parts) and sodium glycolate starch (10 parts) were mixed into the mixture. Half of this mixture was granulated by compression and sieved through sieve No. 10 and then mixed with the remaining half, mixed and compressed into tablets using a 9.0 mm or 11.0 mm standard concave punches and dies. The tablets were heated, film-coated by spraying a mixture of a mixture of methanol (1 liter) and dichloromethane (1 liter) containing hydroxypropylmethylcellulose (60 g), ethylcellulose (15 g), diethyl phthalate (9 g) and an approved colorant, followed by rotation. in finely ground carnauba wax. Using a 9.0 mm mold, tablets containing 127 mg of dihydrochloride monohydrate were obtained, and using a 64585 12 11.0 mmsn mold, tablets containing 254 mg of dihydrochloride monohydrate were obtained.

Example 12

The pharmaceutical composition for intravenous administration was prepared by the following method. Racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinepyridazine dihydrochloride monohydrate was dissolved in freshly distilled water to give a solution of 12.74 mg dihydrochloride monohydrate per milliliter, and the solution was filtered. As an 8 micron filter and then placed in 5 ml quartz glass ampoules under a nitrogen atmosphere. The ampoules were heat sealed and sterilized at 115-116 ° for 30 minutes. Alternatively, a solution of 31.86 mg dihydrochloride monohydrate per milliliter was prepared and sealed in 2 ml ampoules.

Example 13

For oral administration, a pharmaceutical composition was prepared by mixing racemic 3- [2- (3-t-butylamino-2-hydroxypropoxy) phenyl] -6-hydrazinepyridazine dihydrochloride monohydrate (100 parts) with lactose (30 parts) and magnesium stearate (1 part). part). The mixture was screened and filled into No. 1 hard shell gelatin capsules so that each capsule contained 254 mg of dihydrochloride monohydrate.